AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients

Abstract

Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty-three patients (60% female; ages 6 months-36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0-12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises were present in 97% of patients aged 2 to 12 years, occurred in the majority of patients in all age groups, and tended to be most severe during early childhood. Prominent non-motor symptoms were sleep disturbance, irritable mood, and feeding difficulties. The majority of subjects (70%) had profound motor impairment characterized by absent head control and minimal voluntary movement, while 17% had mild motor impairment and were able to walk independently. Dopamine agonists were the medications most likely to produce some symptomatic benefit, but were associated with dose-limiting side effects (dyskinesia, insomnia, irritability, vomiting) that led to discontinuation 25% of the time. The age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease.

Keywords: dystonia-parkinsonism; gene therapy; natural history; neurotransmitter disorders; rare diseases.

FIGURE 1

Subject age distribution and latency to diagnosis. A, Subject age ranged from 6 months to 36 years. There is a skew toward younger age (48% of subjects younger than 6 years, 70% younger than 13 years). B, Latency from symptom onset to diagnosis has decreased in the past decade; most subjects over age 10 years experienced a delay of years between symptom onset and diagnosis

FIGURE 2

Motor and non‐motor symptoms. A, Reported prevalence of initial symptoms (n = 52). B‐F, Reported prevalence of current non‐motor symptoms across age groups (n = 51). Major (dark gray): frequent and/or severe, with significant impact on comfort or function; Minor (light gray): minor and/or infrequent

FIGURE 3

Oculogyric Crises (OGC). A, Reported current prevalence of OGC's across age groups (n = 57): 91% of subjects under 18, 60% of subjects over 18. B and C, OGC duration and frequency, respectively, in younger (age < 6 years, dark gray) vs older (age ≥ 6 years, light gray) subjects. Over 80% of younger subjects experienced prolonged episodes (> 4 hours duration), and the majority experienced episodes at least three times per week